The major histocompatibility complex (MHC) plays key roles in controlling both adaptive and innate immune systems. In the adaptive immune system, both MHC class I and class II antigens recognize, bind and present peptides to cytotoxic and helper T-cells, respectively, and initiate cell-to-cell communication between antigen presenting cells and T-cells by forming immunological synapses and activating both subtypes of T-cells for cellular and humoral immune systems. More recently, a variety of host restriction genes have been identified in humans and mammals that modulate retrovirus infectivity, replication, assembly and/or cross-species transmission. One of these host encoded genes, Apolipoprotein B mRNA-editing enzyme catalytic (APOBEC2) is capable of terminally editing feline foamy virus in the absence of virally-encoded Bet protein, but not in its presence, similar to the interplay of APOBEC3 and the HIV-encoded protein Vif. The editing capacity of APOBEC3 appears to be species specific and limits cross-species transmission of retroviruses. To identify and characterize APOBEC genes in the feline genome, we attempted APOBEC-related sequences in the scaffolds of the partial (2x) genome sequence of the domestic cat and compared these phylogenetically to their human and dog counterparts. (A) Comparative Genomic Structure of the MHC Comparisons of the genomic structure of three mammalian MHC, human leukocyte antigens (HLA), canine dog leukocyte antigens (DLA), and feline leukocyte antigens (FLA) revealed remarkable structural differences between HLA and the other two MHC. The 4.6 Mb HLA sequence was compared with the 3.9 Mb DLA sequence from two supercontigs generated by 7x whole genome shotgun assembly and 3.3 Mb FLA draft sequence. For FLA, we confirm that: (i) feline FLA was split into two pieces within the TRIM gene family found in human HLA; (ii) class I, II, and III regions were placed in the pericentrocentric region of the long arm of chromosome B2; and (iii) remaining FLA was located in subtelomeric region of the short arm of chromosome B2. The exact same chromosome break was found in canine DLA structure, where class I, II, and III regions were placed in a percentromeric region of chromosome 12, while the remaining region was located in a subtelomeric region of chromosome 35, suggesting this chromosome break occurred once before a split of felid and canid more than 55 MYA. However, significant differences were found in the content of genes in both pericentromeric and subtelomeric regions in DLA and FLA, the gene number and amplicon structure of class I genes plus two other class I genes found on two additional chromosomes; canine chromosome 7 and 18, suggests the dynamic nature in the evolution of MHC class I genes. (B) Sequences, Annotation and Single Nucleotide Polymorphism (SNP) of the MHC in the Domestic Cat Two sequences of the MHC regions in the domestic cat, 2.976 and 0.362 Mbps, which were separated by an ancient chromosome break (55 - 80 MYA) and followed by a chromosomal inversion were determined by bacterial artificial chromosome (BAC) shotgun sequencing. Gene annotation of this MHC was completed and identified 317 possible coding regions (128 human homologues, possible functional genes and 189 pseudo/unidentified genes) by GENSCAN, BLASTN, and BLASTP programs. The first region spans 2.976 Mbp sequence, which encodes six classical class II antigens (three DRA and three DRB antigens), nine antigen processing molecules (DOA/DOB, DMA/DMB, TAPASIN, and LMP2/LMP7.TAP1/TAP2), 52 class III genes, 19 class I antigens (FLAI-A to FLAI-S). Two class I genes (FLAI-H, I-K) were transcribed in a feline fibroblast cell line and one (FLAI-E) had a peptide binding site structure similar to the classical class I gene. The second region spans 0.362 Mbp sequence encoding no class I genes and 18 framework genes, including three olfactory receptor genes. One previously identified feline endogenous retrovirus, a baboon retrovirus derived sequence (ECE1) and two new endogeneous retrovirus sequences, both of which showed high sequence similarity to brown bat endogeneous retrovirus (FERVmlu1, FERVmlu2) were found within a 100 Kbp interval in the middle of class I region. MHC SNPs were examined based on comparisons of this BAC sequence and MHC homozygous 2 X whole genome scan (WGS) sequences and found that 11,654 SNPs in 2.84 Mbp (0.00411 SNP per bp), which is 2.4 times higher rate than average heterozygous region in 2 X WGS (0.0017 SNP per bp genome), and slightly higher than the SNP rate observed in human MHC (0.00337 SNP per bp). (C) Functions, Structure, and Read-Through Alternative Splicing of Feline APOBEC3 Genes Over the last few years, a variety of host restriction genes have been identified in human and mammals that modulate retrovirus infectivity, replication, assembly and/or cross-species transmission. One of the host encoded proteins, APOBEC3 (A3, Apoliporoteins B mRNA-editing catalytic polypeptide) is a potent inhibitor of retroviruses and retrotransposons. While primates encode seven genes (A3A to H), rodents carry only a single A3 gene. Here we identified and characterized several A3 genes in the feline genome by characterizing the 50k genomic A3 locus. We detected that the domestic cat (<i>Felis catus</i>) has three very similar A3C genes (a c) probably generated by two consecutive gene duplications and one A3H gene. In addition to these four one-domain A3 proteins, a fifth A3, designated A3CH, is expressed by a read-through alternative splicing. Using reporter systems for feline retroviruses, we found that specific feline A3 proteins selectively inactivate only defined subgroups of feline retroviruses: Bet-deficient feline foamy virus was inactivated by feA3Ca, -b and c, but not by feA3H or feA3CH. The infectivity of Vif-deficient feline immunodeficiency virus and feline leukemia virus was reduced only by feA3H and feA3CH, but not by any of the feA3Cs. We compared the phylogeny of cat A3s with their counterparts in other felid species. As anticipated, the feline A3C sequences show significant adaptive evolution, but unexpectedly, the A3H sequences contain more sites which are under purifying evolution probably reflecting differences in the respective host virus co-evolution. In contrast to cats, dogs encode only A3A and A3H which may be related to the fact that there are no exogenous retroviruses of dogs present